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Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases

Previous research on animal and physiological models suggests that antioxidant supplements have beneficial effects that may prolong life. Some observational studies also suggest that antioxidant supplements may prolong life, whereas other observational studies demonstrate neutral or harmful effects. Our Cochrane review from 2008 demonstrated that antioxidant supplements seem to increase mortality. This review is now updated.

The present systematic review included 78 randomised clinical trials. In total, 296,707 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase (including gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified diseases). A total of 21,484 of 183,749 participants (11.7%) randomised to antioxidant supplements and 11,479 of 112,958 participants (10.2%) randomised to placebo or no intervention died. The trials appeared to have enough statistical similarity that they could be combined. When all of the trials were combined, antioxidants may or may not have increased mortality depending on which statistical combination method was employed; the analysis that is typically used when similarity is present demonstrated that antioxidant use did slightly increase mortality (that is, the patients consuming the antioxidants were 1.03 times as likely to die as were the controls). When analyses were done to identify factors that were associated with this finding, the two factors identified were better methodology to prevent bias from being a factor in the trial (trials with ‘low risk of bias’) and the use of vitamin A. In fact, when the trials with low risks of bias were considered separately, the increased mortality was even more pronounced (1.04 times as likely to die as were the controls). The potential damage from vitamin A disappeared when only the low risks of bias trials were considered. The increased risk of mortality was associated with beta-carotene and possibly vitamin E and vitamin A, but was not associated with the use of vitamin C or selenium. The current evidence does not support the use of antioxidant supplements in the general population or in patients with various diseases.

Authors' conclusions:

We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.

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Background:

Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.

Objectives:

To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.

Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity.

For 20 years, Cochrane has produced systematic reviews of primary research in human health care and health policy, and these are internationally recognized as the highest standard in evidence-based health care resources. Read more...